Amino Acids Regulate mTORC1 by an Obligate Two-step Mechanism

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) coordinates cell growth with its nutritional, hormonal, energy, and stress status. Amino acids are critical regulators of mTORC1 that permit other inputs to mTORC1 activity. However, the roles of individual amino acids and their interactions in mTORC1 activation are not well understood. Here we demonstrate that activation of mTORC1 by amino acids includes two discrete and separable steps: priming and activation. Sensitizing mTORC1 activation by priming amino acids is a prerequisite for subsequent stimulation of mTORC1 by activating amino acids. Priming is achieved by a group of amino acids that includes L-asparagine, L-glutamine, L-threonine, L-arginine, L-glycine, L-proline, L-serine, L-alanine, and L-glutamic acid. The group of activating amino acids is dominated by L-leucine but also includes L-methionine, L-isoleucine, and L-valine. L-Cysteine predominantly inhibits priming but not the activating step. Priming and activating steps differ in their requirements for amino acid concentration and duration of treatment. Priming and activating amino acids use mechanisms that are distinct both from each other and from growth factor signaling. Neither step requires intact tuberous sclerosis complex of proteins to activate mTORC1. Concerted action of priming and activating amino acids is required to localize mTORC1 to lysosomes and achieve its activation.

Differential accumulation of leucine and methionine in red and green pea aphids leads to different fecundity in response to nitrogen fertilization

“…Free amino acids are precursors for the biosynthesis of low molecular weight nitrogenous substances and hormones . More importantly, they modulate gene expression and protein synthesis via signaling, such as via the TOR pathway . As a result, amino acids are involved in regulating insect development, fecundity and lifespan .…”

“…41 More importantly, they modulate gene expression and protein synthesis via signaling, such as via the TOR pathway. 42 As a result, amino acids are involved in regulating insect development, fecundity and lifespan. 43 The role of individual amino acids in TOR activation is complicated, and whether the effect is positive or neutral may depend on the species of the organism, cell type and amino acid concentration.…”

“…43 The role of individual amino acids in TOR activation is complicated, and whether the effect is positive or neutral may depend on the species of the organism, cell type and amino acid concentration. [42][43][44][45] Among the four essential amino acids that specifically accumulated in the green morph of A. pisum under nitrogen fertilization, Leu has usually been found to have greatest effect on TOR activation. 42,46 The other three amino acids were reported to activate TOR in only a limited number of cases.…”

“…[42][43][44][45] Among the four essential amino acids that specifically accumulated in the green morph of A. pisum under nitrogen fertilization, Leu has usually been found to have greatest effect on TOR activation. 42,46 The other three amino acids were reported to activate TOR in only a limited number of cases. For example, Ile activated TOR pathway in cow bovine mammary tissue but not in human cancer cells; 42,45 Val regulated the TOR pathway in mouse neuron cells but was inactive in most other kinds of cells; 42,47 and Met activated the TOR pathway in mouse myoblasts but not in rainbow trout hepatocytes.…”

“…42,46 The other three amino acids were reported to activate TOR in only a limited number of cases. For example, Ile activated TOR pathway in cow bovine mammary tissue but not in human cancer cells; 42,45 Val regulated the TOR pathway in mouse neuron cells but was inactive in most other kinds of cells; 42,47 and Met activated the TOR pathway in mouse myoblasts but not in rainbow trout hepatocytes. 48,49 In the current study, we micro-injected individual amino acids into aphids to simulate aphids feeding on plants grown with nitrogen fertilization.…”